The retina is a tissue with a thickness of from 0.1 to 0.5 mm which is composed of ten layers of inner limiting membrane, nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, outer limiting membrane, photoreceptor cell layer and retinal pigment epithelium layer, and retinal neuronal cell groups including photoreceptor cells, bipolar cells, ganglion cells, horizontal cells, amacrine cells and Muller cells are present therein.
The retinal neuronal cells play an important role in the reception and transmission of visual information such as converting light stimulation into an electrical signal and transmitting the signal to the brain.
To specifically describe the mechanism of such transmission, the visual information from the eyes is converted into an electrical signal through photoreceptor cells and transmitted to ganglion cells by way of horizontal cells, bipolar cells and/or amacrine cells. Then, the electrical signal is transmitted to the brain by way of the optic nerve which is a bundle of optic nerve fibers including axons of ganglion cells.
When these retinal neuronal cells are damaged due to various causes, the homeostasis (a function to supply oxygen or nutrition to retinal neuronal cells through retinal blood circulation and the like) of retinal neuronal cells cannot be maintained, and the transmission of visual information to the brain is inhibited. For example, it is widely known that dysfunction of retinal neuronal cells is caused in various retinal diseases such as retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, glaucoma, macular degeneration, retinitis pigmentosa and Leber's disease (Brain Res. Bull., 62(6), 447-453 (2004)).
It has recently been considered that retinal neuronal cell death due to retinal ischemia is one of the causes of retinal neuronal cell damage, and the following events and the like have been reported regarding the retinal neuronal cell death due to retinal ischemia (JP-A-2003-146904 and Nature Rev., 2, 448-459 (2003)).
1) The mechanism of retinal neuronal cell death due to retinal ischemia is similar to that of cerebral neuronal cell death during cerebral ischemia.
2) In short term retinal ischemia, the retinal inner layer (inner plexiform layer) is selectively damaged.
3) The excess release of glutamate during retinal ischemia can be observed.
4) By the injection of an excitatory amino acid such as glutamate into the vitreous body, retinal neuronal cell death is induced.
5) The overstimulation mediated by retinal N-methyl-D-aspartate (NMDA) receptors promotes calcium (Ca) influx into cells, which results in inducing cell damage by way of induction of nitrogen monoxide (NO).
From these, it is considered that a drug such as a glutamate neurotoxicity inhibitor, a NMDA receptor antagonist or a NO synthesis inhibitor is useful for the treatment of an eye disease caused by retinal neuronal cell damage, and various studies have been carried out.
For example, JP-A-2001-072591 discloses a protective agent for a retinal neuronal cell comprising nipradilol which is one of the β-blockers as an active ingredient. WO 01/056606 discloses a protective agent for an optic ganglion cell comprising an interleukin-1 receptor antagonist protein as an active ingredient. WO 03/004058 discloses a protective agent for an optic ganglion cell comprising an α1 receptor antagonist such as bunazosin hydrochloride as an active ingredient. Experimental Eye Res., 72, 479-486 (2001) discloses an effect of protecting a neuronal cell of latanoprost which is one of the prostaglandin derivatives, etc.
On the other hand, WO 2005/035506 discloses an indazole derivative as a Rho kinase inhibitor.
However, this publication does not disclose an effect of protecting a retinal neuronal cell of an indazole derivative at all.